Chapter 8

The Madhouse of Science Part 1

(1) Henry Cotton’s Lunacy

(2) Bayes Theorum and the Great Health Hoax

(3) The Non-Validity of the LNT Hypothesis

Andrew Scull

“Psychotics build themselves a castle in the sky, neurotics live in it, and psychiatrists charge rent for it.”

 Andrew Scull is Distinguished Professor of Sociology and Science Studies at the University of California, San Diego. His book about Henry Cotton, Madhouse, will be published by Yale University Press this month.

 On Jan. 11, 1921, at 4:30 in the afternoon, Henry Aloysius Cotton, the superintendent of the New Jersey State Hospital itn Trenton, rose to address a packed House at Princeton. The audience, numbering nearly 400, had assembled in McCosh 10 to hear him deliver the first of four Vanuxem lectures.' Louis Clark Vanuxem 18Z9's bequest in 1912 had endowed a series of annual public lectures at his alma mater, and he had specified that at least half of them were to be on subjects of current scientific interest. Over the course of the 20th century, his generosity would bring a galaxy of distinguished scholars to the university - luminaries like Edwin Hubble, Thomas Hunt Morgan, Robert Oppenheimer, John Von Neumann, Linus Pauling, Harold Urey and Francis Crick. And then there was Cotton, the lone representative of the marginal and often stigmatized field of psychiatry. What explains his presence in the pantheon?

Certainly, Henry Cotton had a glittering resume, at least by the standards of his field. Early training at the University of Maryland and at Johns Hopkins had been followed by an appointment to an extremely

competitive post under the fig­ure who would dominate American psychiatry in the first half of the 20th century, the Swiss-born and -trained Adolf Meyer. Further research in Germany under psychiatrists Emil Kraepelin and Alois Alzheimer gave Cotton a scien­tific pedigree that few "alienists" - the term then used to describe physicians specializing in the treatment of mental disorders - of his age could match. Cotton's selection to head New Jersey's premier asylum, at the age of barely 30, marked him as one of the most promising psychiatrists of his era. On that January day at Princeton, he rose to announce a breakthrough in the understanding and treatment o£ mental disorder, a breakthrough that in his eyes, and the eyes of his sponsors (who included leading scholars in Princeton's biology department), was every bit as important as the advances in astronomy, embryology, game theory, nuclear physics, molecu­lar biology, and chemistry that other Uanuxem lecturers would discourse on.

Not for Cotton the orthodox position embraced by most psy­chiatrists of his age: the belief that major mental disorders were rooted in faulty heredity, in biological defects that marked those suffering from them as degenerate representatives of the human race. But neither did he accept the recently fashionable notion propounded by Freud and his followers: that mental illness was rooted in childhood traumas, in the collision of unconscious forces, in the pathologies of the psyche. There,

in Cotton's view, lay the road to quackery and pseudo-science. Instead, he announced his startling new theory of the origins of mental illness, one that reduced the myriad manifestations of madness to a single underlying cause. Simultaneously, he said,

he had uncovered a straightforward therapeutic that grew directly out of his etiological discoveries, one that promised to cure upwards of 85 percent of cases of psychosis - and even,

if employed prospectively, to eliminate mental disorders altogether.

The key, Cotton argued, was germs. Germs and pus. For years, conservative medical men had resisted the implications of the work of such scientists as Louis Pasteur and Robert Koch, and the warnings about the per­ils of pus in the practice of surgery that emanated from the apostle of antiseptic surgery, Joseph Lister. But by the dawn of the 20th century, the gospel of "germs" was sweeping all before it. Medicine embraced the laboratory as a source of cul­tural authority. Bacteriological models of disease brought gains in'etiological understanding and, to a more limited degree, in therapeutic efficacy. The upshot was that physicians and sur­geons, donning the mantle of the new science, found their pres­tige and their prospects soaring. And yet there were diseases and disorders that remained recalci­trant, resistant to the new paradigm, and frustratingly beyond the reach of modern therapeutics: rheumatism and arthritis, for example, and ather­osclerosis and nephritis.

In the second decade of the 20th century, a number of physicians began to embrace the notion that these conditions, too, were a manifestation of the malevolent impact of germs. The men who advanced this hypoth­esis were anything but marginal Vesicles        figures: They included the dean of the medical school at the University of Chicago and prominent clinicians at such major centers of modern scien­tific medicine as the Mayo Clinic in Minnesota and the medical school in Baltimore. Their conviction grew that a whole array of hitherto mysterious and untreatable illnesses in fact derived from something they called focal sep­sis. Chronic, low-grade infections lurking unnoticed in obscure

regions of the body pumped out poisons - powerful toxins that, as they spread through the bloodstream and the lymph, produced pathological action at a distance, and were thus responsible for a whole array of baffling diseases.

Cotton seems to have encountered these notions sometime around 1915. He was scarcely the only alienist to wonder whether they might have applications in psychiatry, but he was certainly the most aggressive and single-minded in pursuing their implications. He at once set to work to bring blood tests, X-ray machines, microscopes, and test tubes to Trenton, along with an array of outside consultants to help locate and elimi­nate the sources of sepsis. Over the next five years or so, his conviction that he had

uncovered the single source of psychosis hardened into certainty, and he developed a whole range of thera­pies designed to combat the perils of pus infec­tion. At Princeton, he laid his theories and his therapeutic break­throughs before the educated and influen­tial audience that had gathered to hear him speak.

Depression, delu­sions, hallucinations, mania, indeed all man­ner of mental distur­bances were, he informed his listeners, but the surface manifes­tations of an underlying physical disorder of a quite familiar infectious source. More remark­ably still, once the

source of the infection was tracked down and eliminated, the return of mental stability was assured. And in an era that pos­sessed no penicillin or other antibiotics, the process of elimina­tion required a resort to "surgical bacteriology" - put more plainly, cutting out the roots of the trouble.

As early as 1916, Cotton had begun to attack and remove the most obvious site of infection, the teeth: unerupted and impacted teeth; teeth with infected roots and abscesses, decayed or carious teeth, apparently healthy teeth with peri­odontitis, poorly filled teeth, sclerotic teeth, teeth with crowns. When many of his patients stubbornly refused to recover, he was undeterred, redoubling his efforts to locate the underlying focal sepsis he felt certain was there. Tonsils and sinuses were soon joined by spleens and stomachs, colons and cervixes, as he ruthlessly pursued his goal of a thorough cleansing of his patients' bodies. And the results, he informed his rapt Princeton audience, were little short of astonishing. In his final lecture, he reviewed case after case of patients seemingly con­demned to a lifetime of mental darkness who, once relieved of their infected teeth, tonsils, stomachs, or colons, made near­miraculous recoveries.

At the State Hospital, not far from the Princeton campus, a full-fledged surgical assault on sepsis was now the order of the day. Each year, thousands of teeth and tonsils were extracted, and scores of colons and other internal organs sectioned and removed. The payoff, Cotton proclaimed, was a massive increase in the number of cures, and an equally major savings to the state's treasury.

When the New York Times reviewed the published version of Cotton's Princeton lec­tures in June 1922, its reviewer, Thomas Quinn Beesley, had no doubt of their impor­tance: "At the State Hospital at Trenton, NJ., under the brilliant leadership of the medical director, Dr. Henry A. Cotton, there is on foot the most searching, aggressive, and profound scientific investigation that has yet been made of the whole field of mental and nervous disorders." Across the country, others had given way to despair, as rates of mental illness grew four times as fast as the general population, the `limes noted. But thanks to Cotton, it said, "there is hope, high hope ... for the future."

Desperate for relief from the demons that tormented them (or their nearest and dearest), and dazzled by the seemingly authoritative reports emanating from Trenton about the extraordinary breakthroughs associated with a bacteriological model of madness, patients and their families urgently sought to share in the new miracle cures. Affluent madmen and mad­women flocked to Trenton, their numbers originally swelling the ranks of those confined at the State Hospital, where their willingness to pay premium rates for the attention of Cotton and his consultants made them a highly desirable commodity. Across the country, alienists reported that they found them­selves besieged by supplicants seeking the new wonder cure. Frantic families urged that teeth, tonsils, and guts be ransacked for the source of the germs that prompted hallucinations and delusions, ranting and raving, dolor and depression. For so long, madness had seemed a condition beyond help, a source of stigma and shame. If modern biological science had revealed

that it was just another physical affliction, no more than the effects of bacterial poisoning of the brain, then deliverance might be at hand.

The case of Margaret Fisher, one of the first private patients to be transferred to Trenton, illustrates the eagerness with which highly educated and well-connected people arrived to be treated with Cotton's miraculous new therapies, and brought their relations to receive treatment at his hands. Margaret was the daughter of Irving Fisher, a Yale professor lionized by no less a figure than Joseph Schumpeter as "the greatest economist that America has produced." Irving Fisher was an arrogant, humorless, and domineering man who made and eventually lost a fortune exceeding $10 million, enjoyed access to the highest circles of American society, and embraced a host of causes, including Prohibition, eugenics, dietary reform, and the extension of the human life span.

Developing close ties with John Harvey Kellogg, patriarch of the immensely fashionable Battle Creek Sanitarium in Michigan (and founder of the breakfast cereal empire), Fisher had begun in the early 1900s to take his wife and family there each year to partake of the cure. Hydrotherapy, exercise, a veg­etarian diet, close attention to the working of the bowels - all these central elements of Kellogg's regime became a regular part of the Fisher family routine. As a dutiful daughter, Margaret embraced such "healthy" practices at her father's urging.

Still living at home as she entered her 20s, and serving as an unpaid office assistant to her father, Margaret seems to have undergone a slow mental deterioration beginning about 1916. The changes were subtle at first, the onset of her symp­toms insidious and easy to overlook or rationalize. Only in ret­rospect did her parents come to see them as signs of incipient pathology.

On April 27, 1918, Margaret became engaged to be mar­ried. Her parents were delighted, and Margaret's father, having checked the young man's pedigree with one of his oldest friends, urged her to marry as soon as possible. But the prospect seems to have unhinged her. Within days, as Cotton later noted in the last of his Vanuxem lectures (though without mentioning Margaret by name), she began to babble "queer things about portents and was afraid her fiance would not come back [from the war]. She soon began to talk at random about `God, Christ, and immortality,' and reacted to auditory hallucinations. Her conduct was peculiar in many ways. Her condition gradually became worse, and on June 1 she had to be sent to a private hospital."

Thus far, the Fishers had defined her condition as a tempo­rary nervous prostration, and kept her out of any sort of psy­chiatric facility. Unfortunately, however, once hospitalized, as Cotton's case notes recorded, "she became much worse, and could not be controlled" - so their hands were forced. Fisher and his wife concluded "it was necessary to send her to the Bloomingdale Asylum" in White Plains, long regarded by America's plutocrats as a suitable institution for those of their social class. Admitted on June 27, Margaret was "pensive and preoccupied, and at times depressed. She responded slowly to questions and when aroused was irrelevant."

Her psychiatrists soon despaired of her prospects. Noting

the "acute distortion of the patient's personality with marked distortion in thinking, peculiar behavior, and disharmony between mood and thought content," they concluded, as Cotton faithfully noted, that her psychosis "seems more nearly related to the schizophrenic disorders than to the exhaustive or manic-depressive disorders." These were important diagnostic distinctions, since schizophrenia in this era was widely felt

to be an essentially incurable condition. Indeed, the Fishers were informed that "a recovery without defect symptoms seems improbable." Irving Fisher's response was swift: He arranged to have Margaret released from Bloomingdale on March 29, 1919, and that same day she was spirited out of the state and admitted as a private patient to Trenton State Hospital.

Over the years, Fisher had maintained close contacts with

John Harvey Kellogg. In August 1914, for instance, the two men had jointly organized the First International Congress on Racial Betterment in Battle Creek, and Fisher had written for Kellogg's magazine, Good Health. Kellogg, like Cotton, empha­sized the nefarious influence of decayed teeth and the poisons that lurked in the bowels, so when Fisher learned of Cotton's assertions about the etiological connections between focal sep­sis and insanity, and the possibility of intervening to cure the apparently hopeless through a program of surgical bacteriology, he was already primed to accept these claims.

Neurologically, Cotton reported, Margaret Fisher seemed normal. But there was ominous evidence of "marked retention of fecal matter in the colon with marked enlargement of the colon in this area." To be sure, "Because of her resistiveness, X-­ray studies of the intestinal tract could not be made," but Cotton was convinced that the source of a substantial portion of her problems had been uncovered. Proceeding further, he found evidence that her "cervix was eroded." Deeply suspect as well were two unerupted molars, which Cotton immediately

insisted must be extracted. He next approached the Fishers for permission to perform "an exploratory laparotomy [a surgical opening of the abdomen to examine the internal organs] based upon the physical examination and the fact of long-continued constipation."

Irving Fisher and his wife obviously were eager to embrace this somatic account of their daughter's disorder. It provided an etiological account in close accord with their own beliefs about human health, and a far more hopeful prognosis than the one the doctors at the Bloomingdale Asylum had delivered. Still they hesitated to endorse so drastic a remedy as surgery on Margaret's bowels, announcing that they "preferred to wait till other means such as vaccine and serum should be exhausted." In August, however, they did consent to removal of a portion of Margaret's cervix after being advised of the presence of

"pure colon bacillus" in her tissues. The operation was per­formed by Cotton's assistant, Dr. Robert Stone, on Aug. 15, 1919, and the following day, Fisher and Cotton took the train to Battle Creek to consult with Kellogg about how to proceed. Seizing the opportunity presented by their extended time together, Cotton was clearly doing all he could to overcome Fisher's hesitations about further surgery for his daughter. Fisher wrote to his wife, "Dr. C. doesn't think M will suffer any pain. The uterus, like the intestines and other internal organs, has few nerves." Fisher reminded his wife that Cotton believed the bowels were another source of infection that needed attention.

Yet still Margaret's parents hesitated. Back at the hospital, Cotton acknowledged that "the family preferred to wait. ... So in September another course of antistreptococcous [sic] treat­ment was given." Again he urged surgery on the bowels. Again Fisher temporized: "As to operating on M," he wrote to his wife in early October, "we'll talk it over with Dr. C. and each other." And then events took the decision out of their hands.

Perhaps the crisis was iatrogenic, the result of a failure to kill the streptococci before injecting them into poor Margaret's body. In any event, in late October Margaret exhibited symp­toms of inflammation of the lungs, and a deep-seated abscess developed over the ribs on her left side - an abscess that, when lanced and cultured, Cotton recorded, "gave pure strep­tococcus ... the same type found in the teeth and stomach. The condition of the patient did not improve and her temperature continued to be high. She failed rapidly and died on Nov. 7, 1919."

Despite Margaret's death, Cotton believed her case demon­strated the septic origins of psychosis. Fisher, though devastated by the outcome, continued to believe in Cotton's theories, and to insist that there had been a physical cause of his daughter's illness. "Even years later," according to one of Fisher's biogra­phers, Robert Loring Allen, "he wrote his friend Will Eliot that some form of toxemia causes a nervous breakdown." Of course, such sustained faith was a natural psychological defense mechanism in the face of the choices he had made and the treatments he had authorized, but it also reflected how stubbornly Fisher held to his beliefs, not just on this front, but on a whole range of issues. And Fisher was clearly not alone. Legions of other well-to-do Americans followed in his foot­steps, so many that the number of private patients showing up in Trenton to receive treatment began to exceed the capacity of the State Hospital to receive them. As their ranks swelled, Henry Cotton seized the opportunity to open a private hospi­tal in Trenton, an establishment to which the bulk of these paying patients were henceforth referred for treatment.

The claimed cures, of course, were spurious. Yet Cotton continued to pursue focal sepsis with fierce determination for more than a dozen years after his Princeton lectures. None of his professional brethren made more than the feeblest effort to rein him in, even though in further publications, he acknowl­edged that his abdominal surgery was attended with a mortality rate of some 30 percent. (The actual rate, subsequent close study of the hospital records would indicate, was nearly 45 percent.) When Cotton's patron, Adolf Meyer, was presented with a meticulous report from a brave female associate whom he had sent to evaluate the work - a report that showed the approach adopted at Trenton to be useless and massively harmful - he suppressed its findings and allowed the slaughter to proceed. By the time Cotton dropped dead of a heart attack at his private club in Trenton, in May 1933, hundreds of patients had died and thousands more had been maimed. Although abdominal surgery ceased with his death, Cotton's other techniques continued to be used for almost three decades as a succession of his proteges were named superintendent at Trenton. His victims, sadly, included even his own sons, Henry Jr. 3 0 and Adolph '31, stripped of their teeth as a prophylac­tic measure prior to their matriculation at Princeton. Both later killed themselves.

(2)

The Great Health Hoax

 

Insight from the Sunday Telegraph newspaper in Great Britain

Copyright 1998 THE SUNDAY TELEGRAPH (UK)
"The Great Health Hoax"
by Robert Matthews
September 13, 1998

Subhead: Many scientific 'breakthroughs' are nothing but mirages based on flawed research. They result in wasted taxes, false claims for drugs and damaging health scares.

Text: There seemed no doubt about it: if you were going to have a heart attack, there was never a better time than the early 1990s. Your chances of survival appeared to be better than ever. Leading medical journals were reporting results from new ways of treating heart attack victims whose impact on death-rates wasn't just good - it was amazing.

In 1992, trials in Scotland of a clot-busting drug called anistreplase suggested that it could double the chances of survival. A year later, another "miracle cure" emerged: injections of magnesium, which studies suggested could also double survival rates. Leading cardiologists hailed the injections as an "effective, safe, simple and inexpensive" treatment that could save the lives of thousands.

But then something odd began to happen. In 1995, the Lancet published the results of a huge international study of heart attack survival rates among 58,000 patients - and the amazing life-saving abilities of magnesium injections had simply vanished. Anistreplase fared little better: the current view is that its real effectiveness is barely half that suggested by the original trial.

In the long war against Britain's single biggest killer, a few disappointments are obviously inevitable. And over the last decade or so, scientists have identified other heart attack treatments which in trials reduced mortality by up to 30 per cent.

But again, something odd seems to be happening. Once these drugs get out of clinical trials and onto the wards, they too seem to lose their amazing abilities.

Last year, Dr Nigel Brown and colleagues at Queen's Medical Centre in Nottingham published a comparison of death rates among heart attack patients for 1989-1992 and those back in the clinical "Dark Ages" of 1982-4, before such miracles as thrombolytic therapy had shown success in trials. Their aim was to answer a simple question: just what impact have these "clinically proven" treatments had on death rates out on the wards?

Judging by the trial results, the wonder treatments should have led to death rates on the wards of just 10 per cent or so. What Dr Brown and his colleagues actually found was, to put it mildly, disconcerting. Out on the wards, the wonder drugs seem to be having no effect at all. In 1982, the death rate among patients admitted with heart attacks was about 20 per cent. Ten years on, it was the same: 20 per cent - double the death rate predicted by the clinical trials.

In the search for explanations, Dr Brown and his colleagues pointed to the differences between patients in clinical trials - who tend to be hand-picked and fussed over by leading experts - and the ordinary punter who ends up in hospital wards. They also suggested that delays in patients arriving on the wards might be preventing the wonder drugs from showing their true value.

All of which would seem perfectly reasonable - except that heart attack therapies are not the only "breakthroughs" that are proving to be damp squibs out in the real world.

Over the years, cancer experts have seen a host of promising drugs dismally fail once outside clinical trials. In 1986, an analysis of cancer death rates in the New England Journal of Medicine concluded that "Some 35 years of intense effort focused largely on improving treatment must be judged a qualified failure". Last year, the same journal carried an update: "With 12 more years of data and experience", the authors said, "We see little reason to change that conclusion".

Scientists investigating supposed links between ill-health and various "risk factors" have seen the same thing: impressive evidence of a "significant" risk - which then vanishes again when others try to confirm its existence. Leukaemias and overhead pylons, connective tissue disease and silicone breast implants, salt and high blood pressure: all have an impressive heap of studies pointing to a significant risk - and an equally impressive heap saying there isn't.

It is the same story beyond the medical sciences, in fields from psychology to genetics: amazing results discovered by reputable research groups which then vanish again when others try to replicate them.

Much effort has been spent trying to explain these mysterious cases of The Vanishing Breakthrough. Over-reliance on data from tiny samples, the reluctance of journals to print negative findings from early studies, outright cheating: all have been put forward as possible suspects.

Yet the most likely culprit has long been known to statisticians. A clue to its identity comes from the one feature all of these scientific disciplines have in common: they all rely on so-called "significance tests" to gauge the importance of their findings.

First developed in the 1920s, these tests are routinely used throughout the scientific community. Thousands of scientific papers and millions of pounds of research funding have been based on their conclusions. They are ubiquitous and easy to use. And they are fundamentally and dangerously flawed.

Used to analyse clinical trials, these textbook techniques can easily double the apparent effectiveness of a new drug, and turn a borderline result into a highly "significant" breakthrough. They can throw up convincing yet utterly spurious evidence for "links" between diseases and any number of supposed causes. They can even make lend impressive support to claims for the existence of the paranormal.

The very suggestion that these basic flaws in such widely-used techniques could have been missed for so long is astonishing. Altogether more astonishing, however, is the fact that the scientific community has been repeatedly warned about these flaws - and has ignored them.

As a result, thousands of research papers are being published every year whose conclusions are based on techniques known to be unreliable. The time and effort - and public money - wasted in trying to confirm the consequent spurious findings is one of the great scientific scandals of our time.

The roots of this scandal are deep, having their origins in the work of an English mathematician and cleric named Thomas Bayes, published over 200 years ago. In his "Essay Towards Solving a Problem in the Doctrine of Chances", Bayes gave a mathematical recipe of astonishing power. Put simply, it shows how we should change our belief in a theory in the light of new evidence.

One does not need to be a statistician to see the fundamental importance of "Bayes's Theorem" for scientific research. From studies of the cosmos to trials of cancer drugs, all research is ultimately about finding out how we should change out belief in a theory as new data emerge.

For over 150 years, Bayes's Theorem formed the foundation of statistical science, allowing researchers to assess the meaning of new results. But during the early part of this century, a number of influential mathematicians and philosophers began to raise objections to Bayes's Theorem. The most damning was also the simplest: different people could use Bayes's Theorem and get different results.

Faced with the same experimental evidence for, say, ESP, true believers could use Bayes's Theorem to claim that the new results implied that telepathy is almost certainly real. Sceptics, in contrast, could use Bayes's Theorem to insist they were still not convinced.

Both views are possible because Bayes's Theorem shows only how to alter one's prior level of belief - and different people can start out with different opinions.

To non-scientists, this may not seem like an egregious failing at all: what one person sees as convincing evidence may obviously fail to impress others. No matter: the fact that Bayes's Theorem could lead different people to different conclusions led to its being inextricably linked to the most rebarbative concept known to scientists: subjectivity.

It is hard to convey the emotions roused within the scientific community by the S-word. Subjectivity is seen as the barbarian at the gates of science, the enemy of objective truth, the destroyer of insight. It is seen as the mind-virus that has turned the humanities an intellectual free-for-all, where the idea of "progress" is dismissed as bourgeois, and the belief in "facts" naïve. Once allowed into the citadel of science, runs the argument, subjectivity would turn all research into glorified Lit. Crit.

By the 1920s, Bayes's Theorem had all but been declared heretical - which created a problem: what were scientists going to replace it with? The answer came from one of Bayes's most brilliant critics: the Cambridge mathematician and geneticist, Ronald Aylmer Fisher - and father of modern statistics.

Few scientists had greater need of a replacement for Bayes than Fisher, who frequently worked with complex data from plant breeding trials. Drawing on his great mathematical ability, he set about finding a new and completely objective way of drawing conclusions from experiments. By 1925, he believed he had succeeded, and published his techniques in a book, "Statistical Methods for Research Workers". It was to become one of the most influential texts in the history of science, and laid the foundations for virtually all the statistics now used by scientists.

On the face of it, Fisher had achieved what Bayes claimed was impossible: he had found a way of judging the "significance" of experimental data entirely objectively. That is, he had found a way that anyone could use to show that a result was too impressive to be dismissed as a fluke.

All scientists had to do, said Fisher, was to convert their raw data into something called a P-value, a number giving the probability of getting at least as impressive results as those seen by chance alone. If this P-value is below 1 in 20, or 0.05, said Fisher, it was safe to conclude that a finding really was "significant".

Combining simplicity with apparent objectivity, Fisher's P-value method was an immediate hit with the scientific community. Its popularity endures to this day. Open any leading scientific journal and you will see the phrase "P < 0.05" - the hallmark of a significant finding - in papers on every conceivable area of research, from astronomy to zoology. Every year, new statistics textbooks appear to explain Fisher's simple little recipe to a new generation of researchers.

But just as scientists were adopting P-values, a few awkward question started to be asked by other statisticians. The most telling was raised by the distinguished Cambridge mathematician Harold Jeffreys. Writing in his own treatise on statistics, Theory of Probability, published in 1939, Jeffreys asked an obvious question: just why should the dividing line for significance be set at Fisher's value of 0.05 ?

This seemingly innocuous question has profound implications, for Fisher's figure of 0.05 is still the sine qua non for deciding if a scientific result is "significant". All scientists know that if their experiment gives a P-value meeting Fisher's standard they are on their way to having a publishable paper.

Fisher's standard is even more important for pharmaceutical companies, as national regulatory organisations still use Fisher's 0.05 figure to decide whether to approve a new drug for general release. Getting drug trial results with P-values that beat Fisher's standard can thus make the difference between millions in profits or bankruptcy.

So just what were the brilliant insights that led Fisher to choose that talismanic figure of 0.05, on which so much scientific research has since stood or fallen ? Incredibly, as Fisher himself admitted, there weren't any. He simply decided on 0.05 because it was mathematically convenient.

The implications of this are truly disturbing. It means that key scientific questions such as whether a new heart drug is seen as effective or whether diet really is linked to cancer are being decided by an entirely arbitrary standard chosen over 70 years ago for mathematical "convenience".

This would not matter if Fisher had been lucky, and chosen a figure that makes the risk of being fooled by a fluke result very low. Yet statisticians now know that his choice was a particularly bad one - and that many supposedly "significant" findings are in fact entirely spurious.

The first hints of this deeply worrying feature of Fisher's methods first emerged as long ago as the early 1960s, following a resurgence of interest in Bayes's Theorem. Many of the supposedly "insuperable" objections to its use were shown to be baseless, and the theorem has since emerged as one of the axioms of the entire theory of probability. As such, its implications for statistics cannot be wished away - no matter how noisome scientists might find them.

And the most important of those implications is that - as Bayes himself had insisted 200 years ago - it is indeed impossible to judge the "significance" of data in isolation. Crucially, the plausibility of the data has to be taken into account.

Using Bayes's Theorem, a number of leading statisticians began to probe the reliability of P-values as a measure of significance. What they discovered could hardly be more serious.

On the face of it, Fisher's standard of 0.05 suggests that the chances of mere fluke being the real explanation for a given result is just 5 in 100 - plenty of protection against being fooled. But in 1963, a team of statisticians at the University of Michigan showed that the actual chances of being fooled could easily be 10 times higher. Because it fails to take into account plausibility, Fisher's test can see "significance" in results which are actually over 50 per cent likely to be utter nonsense.

The team - which included Professor Leonard Savage, one of the most distinguished experts on probability of modern times - warned researchers that Fisher's little recipe was "startlingly prone" to see significance in fluke results.

Despite being published in the prestigious Psychological Review, it was a warning that went unheeded. Over the next 30 years, other statisticians have also tried to sound the alarm bell, again without success. During the 1980s, Professor James Berger of Purdue University - a world authority on Bayes's Theorem - published a entire series of papers again warning of the "astonishing" tendency of Fisher's P-values to exaggerate significance. Findings that met the 0.05 standard, said Berger, "Can actually arise when the data provide very little or no evidence in favour of an effect".

Again, the warnings were ignored.

In 1986, one scientist decided to take direct action against the failings of Fisher's methods. Professor Kenneth Rothman of the University of Massachusetts, editor of the well-respected American Journal of Public Health told all researchers wanting to publish in the journal that he would no longer accept results based on P-values.

It was a simple move that had a dramatic effect: the teaching in America's leading public health schools was transformed, with statistics courses revised to train students in alternatives to P-values. But two years later, when Rothman stepped down from the editorship, his ban on P-values was dropped - and researchers went back to their old ways.

It has been a similar story in Britain. In 1995, the British Psychological Society and its counterpart in America quietly set up a working party to consider introducing a ban on P-values in its journals. The following year, it was disbanded - having made no decision. "It just sort of petered out", said one insider. "The view was that it would cause too much upheaval for the journals".

Leading British medical journals have also examined the idea of banning P-values, but they too have pulled back. Instead, they merely suggest that researchers use other means of measuring significance. Yet these alternative methods are know to suffer similar flaws to P-values, exaggerating both the size of implausible effects and their significance.

More than 30 years after the first warnings were sounded, it has become clear that the scientific community has no intention of dealing with the flaws in significance tests. Yet the evidence of those flaws is everywhere to be seen: flaky claims of health risks from a host of implausible causes, "wonder drugs" that lose their amazing abilities outside clinical trials, bizarre "links" between genetics and personality.

A striking feature of the excuses given for the lack of action is that they centre on issues like "upheaval for our journals" and the "radical changes" needed in the training of scientists. Curiously for a profession supposedly dedicated to discovering truths, issues such as "reliability of research conclusions" are never mentioned.

It is hard to avoid the conclusion that the real explanation for all the foot-dragging is not scientific at all. It is simply that if scientists abandon significance tests like P-values, many of their claims would be seen for what they really are: meaningless flukes on which tax-payers' money should never have been spent.

The plain fact is that in 1925 Ronald Fisher gave scientists a mathematical machine for turning baloney into breakthroughs, and flukes into funding. It is time to pull the plug.

Robert Matthews' full account of the issues raised in this article, "Facts versus Factions: the use and abuse of subjectivity in scientific research", is available from the European Science and Environment Forum, 4 Church Lane, Barton, Cambridge CB3 7BE, price 3 pounds.

(3)

About the Validity of the LNT Hypothesis

Gunnar Walinder, PhD, with John Ahlquist, CHP

A fundamental doctrine within the radiation protection community (the linear no-threshold [LNT] hypothesis) originally arose in the 1950s. Two congresses were held in Stockholm, in 1952 and 1956 (Advances in Radiobiology 1957). The dominant personality at these meetings was the Nobel Prize winner Hermann J. Muller. The report, Advances in Radiobiology, from the 1956 congress was dedicated to Muller.

In 1927 Muller reported that x rays could induce mutations in male fruit flies. In his investigations Muller found that the mutation rate among the male fruit flies was linearly related to the radiation dose. Furthermore, he could not find any threshold doses, that is, doses below which mutations could be excluded. The reputation of Muller helped lead to a widespread adoption of this linear no-threshold model as a generally valid relationship between radiation doses and genetic effects. A very simple reasoning led to the conclusion that this should be true also with regard to basically genetic diseases as cancer. At this time, the general understanding of carcinogenesis was that it is a process by which one normal cell, in one step, transforms into a malignant state (a malignant phenotype).

Probably, under the influence of the target theory, the genetic effects—no matter whether they lead to congenital damage or cancer—were considered to be stochastic. They were the result of an "all or nothing" event. Consequently, stochastic effects in irradiated populations could be studied by statistical models. The statistical variations were accordingly not a consequence of variations in the human sensitivity to radiogenic cancer. On the contrary, they were considered entirely independent of such variations. Ionizing radiation could increase the rate of tumors, however, not their severity. Thus, the radiogenic cancer could be arithmetically added to the existing cancer rate.

This was exactly what the target theory had predicted with respect to lethal effects in irradiated prokaryotes and in isolated, eukaryotic cells. However, already in the 1950s the theory had become discredited since it did not "work" in higher organisms or, perhaps more correctly speaking, in the presence of water. Accordingly, most of the genetic and tumorigenic effects in higher organisms were not direct effects of the ionizations but mediated by radicals produced by the ionizations. However, if so, the genetic effects of the ionizations could not be stochastic. Instead, they were highly dependent on the actual state of the cell and on the presence of other intracellular substances—for example, oxygen, amines, etc.

Muller carried out his investigations with male fruit flies. Had Muller used female fruit flies, he would have discovered that no mutations whatsoever would have appeared after radiation doses below about 800 mSv. That was what Seymour Abrahamson later found in female fruit flies and W.L. and L.B. Russell found in female mice. This has led the United Nations Scientific Committee on the Effects of Atomic Radiation to present two entirely different tables for genetic effects, one for men and another for women. Considering Muller’s great influence, would we then have had a radiation protection doctrine which had stated that low radiation doses cannot induce genetic damage and cancer? Is the idea of the absence of threshold doses only a matter of chance? If so, this is only another example in the biological science of how general conclusions have been drawn from single experiments and/or from single strains and sexes.

However, there were many people who were reluctant to accept the new idea of the LNT. Rolf Sievert found it difficult to reduce complex biological phenomena such as heredity and cancer to a straight line. He simply did not believe in stochastic, biological effects and his arguments were very similar to those later expressed by Lauriston Taylor. The same opposition could also be found among the oncologists at Radiumhemmet in Stockholm, of whom the perhaps most eloquent spokesman was Dr. Lars-Gunnar Larsson. They claimed that the drawing of straight lines has nothing to do with biology and such methods could never constitute a model of a biological process and, least of all, the complex kind of dysdifferentiation that we call cancer.

Due to my youth and limited experience, I kept silent about the controversy. However, Sievert noticed my hesitation and we had some discussions where we aired our reluctance to stochastic, biological models, however from somewhat different bases. At this time I was working as a mathematical physicist with some interest in physical epistemology. I was puzzled by the fact that people seemed to be fundamentally unaware of what has been going on within this field since the 1880s.

When speaking with scientists about philosophy and epistemology they usually look somewhat absentminded and mumble something about metaphysical blatherskite. However, exactly the same reluctance was the reason why the physicists in the end of the 19^th century criticized the old theory of knowledge. The famous physicist and thinker Ernst Mach (1959; 1970) brought his fist down on the table and said that we have to terminate all these metaphysical theories of knowledge and system buildings. We have no need for speculations. What we really need are objective facts and scientific analyses. We cannot acquire knowledge of the nature and the things themselves but only of our sensory impressions of them.

In this respect, his views were soon approved by almost all physicists and by many epidemiologists. Some decades later, Niels Bohr pointed out the same thing by saying that physics does not deal with nature but with what we can know about it.

In his comprehensive work Die Prinzipien der Mechanik, Heinrich Hertz (1894; 1956) was able to show that mathematics could be used as a consistent and general model of mechanics. Boltzmann did show that Hertz’s model could be extended to thermodynamics (and other branches of physics) by means of statistical mathematics. Mathematics is, of course, not identical with reality-nature; however, it fulfills the necessary conditions (consistency and generality) for such a model. I would say that without this model, modern physics would have been impossible. Hertz did also, very strongly, point out the limitations of the mathematical model. For example, mathematical and physical methods could not be applied to even the simplest living organism. This conclusion has, again and again, been repeated by subsequent physicists. It has puzzled me a great deal that no physicist working in the field of radiation protection seems to have been aware of this fundamental, epistemological principle of the 20th century physics.

Still, 50 years later, the basic doctrine in the radiation protection is expressed (after low doses and dose-rates) by the simple formula:

N = 0.05 × D

where N is the number of radiogenic cancer cases and D is the collective dose (expressed in manSv).

This formula is considered valid for all populations and independent of living habits and other factors that normally are considered of significance for tumor formation. Advocates of this equation cannot possibly have any knowledge of the generic category of disparate diseases which we have given the common name cancer. Nor can they have any idea about the epistemological prerequisites for using mathematical models. As a physicist I have, of course, always applied mathematics to my problems. However this mathematics has to be adjusted to the specific task. To me, it is impossible to understand how one and the same formula can be used as a collective model for all disparate forms of cancer. How should we explain the fact that various forms of cancer have different dose-response relationships and that some tumors cannot, on the whole, be induced by ionizing radiation (for example, such common forms as the uterine cancer and those in the prostate). How can anyone believe that such extremely complex processes as the general carcinogenesis can be adequately described by an equation of the first degree? This model obviously does not fulfill any demands for consistence or generality. The formula is not only generally considered valid, it is also said to be applicable at "homoeopathic"radiation doses. What an unbelievable pretension to knowledge: "We know everything and we are able to give quantitative figures of infinitesimally small radiation risks." It reminds me of MoliPre’s comedies. Could we not hope that, in a reasonably short future, such pretensions of knowledge will give rise to the same roar of laughter as is the case with the precious figures in MoliPre’s comedies? In no other scientific field have such deeply unscientific claims been made.

Of course, we don’t know everything and we can, on grounds of principle, never achieve knowledge of everything. There are epistemological limits in the biology as in all other science. This must be realized and we are scientifically obliged to admit this fact. Radiation risks cannot be treated in a way that differs from all other kinds of risk analyses.

As I have already mentioned above, the primary, interdependent actions between the ionizations and various radicals within the cells preclude the possibility of stochastic interpretations of the observed courses. Modern oncology has also clearly shown that the transformation of a cell into a malignant phenotype is a multistep process that demands several changes in different parts of the genome. All these changes cannot be caused by a low radiation dose. Thus, here too, the malignant contribution of the radiation is dependent on the presence or future emergence of other, necessary genetic effects.

However, the most fundamental uncertainty is connected with the fact that cancer is a group of highly organismic diseases. This is often forgotten by the cytologists who consider malignant cell transformations as synonymous with cancer. However, as the Swedish oncologist Georg Klein (1979) has pointed out, a malignant transformation in vitro is not synonymous with cancer in vivo. A single malignant cell is not synonymous with cancer. Before we can speak of cancer, this transformed cell has to give rise to about one billion divisions; that is, every tumor cell has, as a mean, undergone more than 30 divisions. This is a multi-iterative process with a repeated synthesis of DNA. All iterative processes have two characteristics in common. The outcome of them is unpredictable and a small, often-undetectable factor (technical term: friction) can totally change this outcome. Also for this reason the malignant outcome of a low radiation dose is, on grounds of principle, fundamentally unpredictable. Murray Gell-Mann has defined cancer as A multi-iterative process in a complex, adaptive system (organism). This uncontrolled growth is the basic characteristic of a malignant, fatal development.

It has often been said that it can only be a value, per se, if we apply a model that is more safe than necessary. However, this argument loses its weight when it leads to an incautious cautiousness, that is, when the measures to get below the maximum permissible radiation doses or keep action levels implies greater dangers than those connected with the radiation. There are many examples. The World Health Organization and the International Atomic Energy Agency have estimated that more than 100,000 entirely unnecessary abortions were done in Europe after the Chernobyl accident. Many energy sources (including CO₂- and SO₂-producing fossil fuels) have been preferred to nuclear power. After the Chernobyl accident some people were evacuated to Kiev from low-contaminated, rural areas in the Ukraine, in spite of the fact that the cancer rate in cities like Kiev is 20 to 30% higher than that in rural areas. Many other examples can be given.

Conclusions

1. Mathematical models cannot be applied to living organisms and fundamental living processes like differentiation, as well as to such dysdifferentiations that may lead to cancer.

2. On grounds of principle, the outcome of multi-iterative processes like cancer cannot be predicted at low levels of exposure.

The LNT hypothesis is thus a primitive, unscientific idea that cannot be justified by current scientific understanding. As practiced by the modern radiation protection community, the LNT hypothesis is one of the greatest scientific scandals of our time.

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References

de Hevesy G, Forsberg A, Abbatt J, eds. Advances in radiobiology; 1957.

Hertz H. Die prinzipien der mechanik (Gesammelte Werke III); 1894. Am. Edition: Cohen RS, ed. The principles of mechanics presented in a new form; 1956.

Klein G. Contrasting effects of host and tumor evolution. In: Fortner JG, Rhoads JE, eds. Accomplishments in cancer research. General Motors Cancer Research Foundation. 123-146; 1979.

Mach E. The analysis of sensations. New York; 1959.

Mach E. My scientific theory of knowledge and its reception by my contemporaries. In: Physical reality: Philosophical essays on twentieth century physics (Red; S. Toulmin). New York; 1970.

Walinder G. Has radiation protection become a health hazard? Madison, WI: Medical Physics Publishing; 2000. P